International Consortium to Identify Genes and Interactions Controlling Oral Clef

描述（由申请人提供）：口裂，包括唇裂（CL）、唇腭裂（CLP）和腭裂（CP），共同代表人类最常见的出生缺陷之一。口裂有一个复杂的和异质性的病因学，有强有力的证据表明遗传和环境的因果因素。候选基因研究和全基因组连锁研究已经产生了令人信服但不一致的证据，即多个基因控制着口腔裂的风险，一些研究已经显示了基因和环境暴露之间相互作用的证据，特别是母亲吸烟和营养素。我们已经组建了一个由经验丰富的调查人员组成的联盟，他们积累了大量的病例及其家庭（主要是病例父母三人组）的DNA样本，这些样本现在可用于全基因组研究，这代表了口腔裂遗传调查的下一个水平。具体目标是：1。对1例孤立性、非综合征性唇裂（CL、CLP或CP）患者及其父母确定的2000个病例-父母三联体进行全基因组分析，采用单核苷酸多态性（SNP）标记的高通量基因分型检测连锁和LD。最初的分析将包括基因效应的个体测试，适当的单倍型分析和新的作图方法，更大的染色体区域，允许人群之间的异质性。2.测试基因与常见母体暴露之间的相互作用，包括维生素补充、吸烟和饮酒（通过访谈收集），这些因素被认为是唇裂的环境风险因素。单组分人群（犹他州）营养状态的血清生物标志物测量的可用性允许对GxE相互作用进行重要的进一步测试。3.测试基因之间的相互作用，这可能解释了文献中关于控制口裂风险的基因的一些相互矛盾的结果。该提案提供了一个独特的机会，以扩大和扩展对控制口裂风险的基因的研究，创造了在人群中快速复制的机会，并将指导对控制正常颅面发育的基因的进一步分子研究。

DESCRIPTION (provided by applicant): Oral clefts, which include cleft lip (CL), cleft lip and palate (CLP) and cleft palate (CP), and collectively represent one of the most common birth defects in humans. Oral clefts have a complex and heterogeneous etiology, with strong evidence for both genetic and environmental causal factors. Candidate gene studies and genome wide linkage studies have yielded compelling but inconsistent evidence that multiple genes control risk to oral clefts, and several studies have shown evidence for interaction between genes and environmental exposures, especially maternal smoking and nutrients. We have assembled a consortium of experienced investigators who have accumulated a very large collection of DNA samples on cases and their families (mostly case-parent trios) that are now available for genome wide studies, which represents the next level of genetic investigation for oral clefts. Specific aims are: 1. To conduct a genome wide analysis on 2000 case-parent trios ascertained through a case with isolated, non-syndromic oral cleft (CL, CLP or CP) and their parents using high throughput genotyping of single nucleotide polymorphic (SNP) markers to test for linkage and LD. The initial analysis will consist of individual tests for gene effects, with appropriately haplotype analysis and novel mapping approaches for larger chromosomal regions that allows for heterogeneity among populations. 2. To test for interaction between genes and common maternal exposures including vitamin supplementation, cigarette smoking and alcohol consumption (collected by interview) which have been implicated as environmental risk factors for oral clefts. Availability of serum biomarker measures of nutritional status from one component populations (Utah) allows important further tests for GxE interactions. 3. To test for interaction between genes that may explain some of the conflicting results in the literature with regard to genes controlling risk to oral clefts. This proposal offers a unique opportunity to expand and extend the search for genes controlling risk to oral clefts, creates the opportunity for quick replication across populations and will direct further molecular studies of genes controlling normal craniofacial development.